Beyond First Responders: Neutrophils Shape Biomaterial-Guided Regeneration

Abstract

Neutrophils have long been regarded as short-lived effector cells responsible for clearing pathogens and inducing acute inflammation. However, emerging evidence has reshaped this paradigm, revealing remarkable neutrophil plasticity and their capacity to actively orchestrate tissue repair and regeneration. Neutrophils modulate angiogenesis, extracellular matrix (ECM) remodeling, macrophage polarization, and resolution of inflammation. Distinct neutrophil subsets-including pro-inflammatory and pro-resolving phenotypes-have been identified, highlighting their dynamic adaptation to microenvironmental cues. Notably, neutrophils contribute to vascular network formation through the release of matrix metalloproteinases, growth factors, reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and specialized pro-resolving mediators (SPMs). In the context of biomaterial implantation, neutrophils are the first immune cells to interact with implanted devices, critically shaping the foreign body response (FBR) and influencing downstream regenerative outcomes. While early tissue engineering strategies aimed to suppress neutrophil recruitment, recent advances in immunomodulatory biomaterials seek instead to harness their plasticity. Approaches include promoting timely apoptosis and efferocytosis, regulating reactive oxygen species and NETs formation, and directing neutrophil polarization toward pro-regenerative phenotypes. This review discusses current insights into neutrophil heterogeneity, their role in vascularization and tissue regeneration, and emerging biomaterial-based strategies designed to modulate neutrophil responses. Understanding and strategically directing neutrophil behavior may represent a pivotal step toward the development of next-generation regenerative therapies.